Problems requiring solution before islet transplantation can be used to treat insulin-dependent diabetes mellitus are, (1) acquisition of adequate amounts of tissue, and (2) the control of allograft rejection. Organ culture of murine and human fetal pancreas results in proliferation and differentiation of islets and loss of acinar tissue. Variation of culture conditions may result in reduction of immunogenicity. On the basis of our previous studies we have selected conditions which result in good islet recovery producing tissue which allows the reversal of experimental diabetes by a single pancreas graft per recipient. In vitro conditions will now be varied to test their effects on reduction of tissue immunogenicity. The basic protocol is to firstly culture fetal mouse pancreas under "ideal" conditions for 7-10 days to allow islet cellt to proliferate and acinar tissue to degenerate and then, under conditions of either high oxygen (90%), low temperature (22-24 degrees C), or combinations of both for 14-21 days, to allow immunogenic "stimulator" cells to degenerate. The tissue is then transplanted into syngeneic and allogeneic diabetic recipients. Syngeneic recipients are used to test the functional capacity of the tissue in the absence of immunologic factors; allogeneic recipients test both the immunogenicity and functional capacity of the graft. Female mice grafted under the renal capsule will be used. Single pancreases whose in vitro insulin and glucagon production has been monitored will be grafted to individual mice. The mice will be assessed by serial blood glucose and insulin levels and, ultimately by microscopic examination of the graft and of various target tissues to assess the offect of the graft on the development of microvascular complications. Organ cultures of human getal pancreases will be used to study their ability to produce insulin and glucagon. The effect of human fetal gestational age and cold ischemia will be assessed. A clinical trial of islet transplantation has been approved on diabetic patients selected on the basis of having a previous renal allograft, or of being on immunosuppression for other resions, or of being at such grave risk of developing serious complications of diabetes that immunosuppression would be judged to be a lesser hazard than continuing poorly controlled diabetes.